The overall goal of this research program is to understand the process of signal transduction by the pro-inflammatory cytokines tumor necrosis factor (TNF) and interleukin 1 (IL-1). The potent biological actions of these cytokines have been studied in detail. However, an understanding of the molecular basis of signal transduction has remained elusive. The long- term goal of this research is to define physiologically relevant signaling mechanisms employed by these cytokines. Recently, we identified a protein kinase that is markedly activated by treatment of cells with TNF or IL-1. This protein kinase, JNK, binds and phosphorylates the amino-terminal activation domain of the transcription factor c-Jun. The phosphorylation of c-Jun by JNK causes increased transcriptional activity and accounts, in part, for cytokine-stimulated gene expression mediated by AP-1. The mechanism of JNK activation by cytokines is mediated by dual phosphorylation on Thr and Tyr. A specific focus of this proposal is to define the functional significance and mechanism of activation of this protein kinase signal transduction pathway. Achievement of the goals of this proposal will increase understanding of signal transduction by cytokine receptors. This information represents a basis for the design of novel therapeutic strategies for the treatment of: 1) inflammation; and 2) proliferative diseases such as psoriasis and cancer. The Specific Aims of this proposal are to examine: 1. The JNK protein kinase cascade. 2. The activation of the JNK pathway by cytokine receptors. 3. The interaction of JNK with other proteins.